The present invention relates to synthetic pheromones or their components and, in particular, to metathesis reactions to produce biologically active compounds and intermediates such as insect sex-attractant pheromones or their components such as E-5-decenyl acetate, the major component of the Peach twig borer pheromone; (5R,6S)-6-acetoxy-5-hexadecanolide, the mosquito oviposition sex attractant pheromone; or E9,Z11-hexadecadienal, the pecan nut casebearer moth pheromone.
Insect pests destroy crops and/or spread disease. Common pest control methods involves spraying farmland, orchards, wetlands, forests, or other pest habitats with insecticides. This method is problematic because insecticides are applied directly to crops or watersheds, and this practice is contrary to an increasing preference for organic produce as well as contrary to water quality issues and other environmental concerns. Insecticides are also nondiscriminate killers and kill beneficial insects as well as harmful insects. Finally, the insect pests are becoming increasingly resistant to many of the common insecticides.
An alternative method to control insect populations involves the use of the insect""s sex attractant to confuse the male insect and thereby prevent mating and eliminate future insect generations. This technique is called mating pattern disruption. Insect pheromones constitute a relatively new class of compounds that have a number of advantages over conventional insecticides. Insect pheromones are nontoxic and environmentally friendly. They are specific to the target insect and do not adversely affect beneficial insects and, they have not been shown to induce the development of resistance in the target insects. The biggest drawbacks in using mating pattern disruption to control insect populations is the cost of producing the insect pheromone, which is typically far more expensive than that of traditional insecticides. Methods that reduce the production costs of insect pheromones would make mating pattern disruption an economical technique for controlling insect populations and thereby minimize environmental concerns associated with pest control.
In general, common pheromones include a 10- to 18-carbon atom-containing olefin that has a terminal alcohol, aldehyde, or acetate functional group and possess a particular stereo-isomerism. The following background is presented herein only by way of example to a few pheromones for common insect pests, such as the Peach Twig Borer (PTB), which is a major pest in stone fruit orchards, and for pathogen-vectoring mosquitoes of genus Culex, and for the Pecan nutcase bearer.moth, which is a major pest in pecans.
PTB pheromone is an 85:15 ratio of E-5-decenyl acetate and E-5-decenol. Thus production of 5-decenyl acetate, which is the major component of PTB pheromone, is a significant step of the PTB pheromone manufacturing process. The acetate can be subsequently removed by hydrolysis to obtain E-5-decenol, the other component of PTB pheromone. A fast, inexpensive, and high yield process for synthesizing E-5-decenyl acetate is, therefore, desirable.
The following background information concerning the Mosquito Oviposition Pheromone (MOP), another highly sought after insect pest pheromone, is largely derived from Olagbemiro, et al. in xe2x80x9cProduction of (5R,6S)-6-Acetoxy-5-hexadecanolide, the Mosquito Oviposition Pheromone, from Seed Oil of the Summer Cypress Plant, Kochia scoparia (Chenopodiaceae),xe2x80x9d J. Agric. Food Chem. (1999) 47, 3411. Please refer to this article for greater detail.
Mosquitoes of the genus Culex (Diptera: Culicidae) pose the greatest threat to public health because of their ability to act as vectors of causative agents for diseases such as malaria, dengue, yellow fever, encephalitis, and filariasis, which afflict many millions of people world-wide. Malaria and encephalitis infect the greatest number of people and have the highest mortality levels, affecting approximately one-third the world""s 1.5 billion people in 90 countries, mainly in Africa. (AAAS (American Association for the Advancement of Science) xe2x80x9cMalaria and Development in Africaxe2x80x9d: AAAS: Washington, D.C., (1991); Giles et al. xe2x80x9cBruce-Chwatt""s Essential Malariologyxe2x80x9d, 3rd Ed.; Edward Arnold; London UK (1993); and WHO/CTD. xe2x80x9cMalaria Prevention and Control,xe2x80x9d WHO Report; Geneva (1998).)
Filariasis has infected 3.33% (i.e. xcx9c15 million people) of the 450 million people at risk, with nearly 1 million new cases occurring annually. (Reeves et al. xe2x80x9cNatural Infection in Arthropod Vector,xe2x80x9d Epidemiology and Control of Mosquito-Borne Arboviruses in California 1943-1987; Reeves, W. G., Ed.; California Mosquito Control Association: Sacramento, Calif. 1990; pp 128-149.) Because of the rapid increase in reported cases of vector caused diseases, efficient techniques for vector surveillance and control are of the utmost importance.
The mosquitoes of Culex quinquefasciatus are responsible for the transmission of Wuchereria bancrofti, the causative agent of human filariasis and St. Louis encephalitis virus and other arboviruses in the United States. (Reisen et al. xe2x80x9cEcology of mosquito and St. Louis Encephalitis virus in Los Angeles basin of California, 1987-1990,xe2x80x9d J. Med. Entomol. (1992) 29, 582.) Gravid Culex quinquefasciatus females use olfactory cues to locate suitable egg-laying sites. The main cue is the oviposition attractant pheromone ((5R,6S)-6-acetoxy-5-hexadecanolide) which is released by mature egg rafts. (Osgood, C. E. xe2x80x9cAn oviposition pheromone associated with the egg rafts of Culex tarsalis,xe2x80x9d J. Econ. Entomol. (1971) 64, 1038; Osgood et al. xe2x80x9cAn Air-Flow Olfactometer for the Distinguishing between Oviposition Attractants and Stimulants of Mosquitoes,xe2x80x9d J. Econ. Entomol. (1971a) 64, 1109; and Starratt, A. N.; C. E. Osgood xe2x80x9c1,3-Diglycerides from the Eggs of Culex pipens quinquefasciatus and Culex pipens pipens,xe2x80x9d Comp. Biochem. Physiol. (1973) 857.)
The oviposition attractant pheromone ((5R,6S)-6-acetoxy-5-hexadecanolide) produced by female mosquitoes of Culex quinquefasciatus is released from apical droplets on the eggs. (Laurence et al. xe2x80x9cErythro-6-acetoxy-5-hexadecanolide the major component of a mosquito oviposition attractant pheromone,xe2x80x9d J. Chem. Soc. Chem. Commun. (1982) 59-60. (Laurence et al. ""82) This attracts other females of this and related species to the vicinity of the laid eggs. (Howse et al. xe2x80x9cInsect Pheromones and their Use in Pest Managementxe2x80x9d Chapman and Hall, 2-6 Boundary Row, London SE1 8HN, UK 1998, p 52.)
New strategies for controlling mosquitoes of Culex quinquefasciatus started with the identification of the oviposition attractant pheromone (5R,6S)-6-acetoxy-5-hexadecanolide. (Laurence et al. ""82; Laurence et al. xe2x80x9cAbsolute Configuration of the Mosquito Oviposition Attractant Pheromone 6-acetoxy-5-hexadecanolide,xe2x80x9d J. Chem. Ecol. (1985) 11,643; and Laurence et al. xe2x80x9cAn Oviposition Attractant Pheromone in Culex quinquefasciatus Say (Diptera, Culicidae),xe2x80x9d Bull. Entomol. Res. (1985a) 75,283.) Laboratory and field trials, in nine countries and three continents, using synthetic pheromone containing an equal ratio of all four stereoisomers [i.e., (5R,6S), (5S,6S), (5R,6R) and (5S,6R)] of (5,6)-6-acetoxy-5-hexadecanolide (Dawson et al. xe2x80x9cConvenient Synthesis of Mosquito Oviposition Pheromone and a Highly Flourinated Analog Retaining Biological Activity,xe2x80x9d J. Chem. Ecol. (1990) 16, 1779.) have demonstrated the efficacy of the oviposition pheromone in attracting Culex spp. mosquitoes. (Otieno et al. xe2x80x9cA Field Trial of the Synthetic Oviposition Pheromone with Culex quinquefasciatus Say (Diptera, Culicidae) in Kenya,xe2x80x9d Bull. Entoniol. Res. (1988) 78, 463.) Despite the presence of the three inactive and unnatural stereoisomers of (5, 6)-6-acetoxy-5-hexadecanolide [i.e., (5S,6S), (5R,6R) and (5S,6R)], the biological activity of the naturally occurring isomer was unaffected. These results demonstrate that an effective, efficacious and inexpensive oviposition attractant pheromone, (5R,6S)-6-acetoxy-5-hexadecanolide, would result from a racemic mixture of (5R,6S)-6-acetoxy-5-hexadecanolide containing its stereoisomers. Also Olagbemiro et al. demonstrated that Culex quinquefasciatus female mosquitoes are unaffected by seed oil impurities and synthetic impurities produced from the synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide and its stereoisomers.
The identification and characterization of the oviposition attractant pheromone provided the impetus for many asymmetric syntheses and large scale racemic synthetic routes. (Laurence et al. ""82; Coutrout et al. xe2x80x9c5-Formyl-d-valerolactonexe2x80x94A Useful Synthon for the Chiral Synthesis of the Vespa orientalis Pheromone and the Mosquito Oviposition Attractant Pheromone,xe2x80x9d Tetrahedron Lett. (1994) 35, 8381; Gravierpelletier et al. xe2x80x9cEnantiopure hydroxylactones from L-ascorbic acid and D-isoascorbic acids: 2. Synthesis of (xe2x88x92)-(5R,6S)-6-acetoxy-5-hexadecanolide and its Diastereomers,xe2x80x9d Tetrahedron (1995) 51, 1663; Henkel et al. xe2x80x9cLipase catalyzed Synthesis of (5R,6S)-6-acetoxyylkan-5-olides-Homologues of the Mosquito Oviposition Attractant Pheromone,xe2x80x9d J. Pract. Chem. (1997) 339, 434-440; Mori, K., xe2x80x9cThe Total Synthesis of Natural Products, Volume 9xe2x80x9d John ApSimon Ed. John Wiley and Sons New York (1992) pp. 252-264, and references therein.) The various synthetic routes cited above can provide multigram quantities of oviposition attractant pheromone, however, the cost of producing them are prohibitive. Therefore, an inexpensive and effective Culex mosquito oviposition pheromone and a synthesis thereof would be greatly desirable.
Another insect pest, the pecan nut casebearer moth (PNCB), Acrobasis nuxvorella Neuzig, is one of the last major pests of the $49 million United States pecan industry that is not controlled by biological means. The PNCB is the key pest of pecans in Texas, Oklahoma, Missouri, Kansas, Arkansas and Louisiana, and it can also impacts crops further east. This pest recently invaded the highly productive pecan Mesilla Valley region of New Mexico. Management of pecan orchards in the west is nearly completely organic, disturbed only by the use of insecticides to control the pecan nut casebearer moth.
The currently effective organophosphate insecticides (i.e. Lorsban E4 and 50W) are under review by EPA through the Food Quality Protection Act and may be removed from the market because of residuals in food products. Pyrethroid insecticides are not a viable alternative because they cause a population explosion of aphids and spider mites after treatment, which are difficult to control in pecans (Knutson A.; W. Ree. 1998. xe2x80x9cManaging insect and mite pests of commercial pecan in Texas,xe2x80x9d Texas Ag Extension Service, B 1238. 13 pp). Soon, pecan growers may not have a viable alternative to control the PNCB. CONFIRM(copyright), an insect growth regulator, is an alternative, but it is expensive and is subject to development of resistance to it when it is the sole method of control employed. If left unchecked, the PNCB could devastate the pecan industry and cause many pecan growers to go out of business. Thus, there is an immediate need to develop a viable and economical alternative to controlling the PNCB.
PNCBs are most damaging during their first generation which occurs during two weeks in late April and early May of mating and egg laying (Knutson, 1988). This treatment window provides a brief and defined period of time when insecticide sprays are capable of controlling PNCB populations by targeting the larvae that hatch before they penetrate nutlets. The recent development of pheromone traps to monitor PNCB population dynamics has transformed the management of pecan orchards, allowing for the accurate timing of insecticide applications. A promising alternative pest management technique is to use the PNCB pheromone to promote mating disruption and thereby controlling its populations.
The PNCB pheromone is E9,Z11-hexadecadienal, a unique pheromone compound. The PNCB pheromone is not commercially available in quantities larger than micrograms. The two companies that sell lures, for monitoring the PNCB are unable to supply the PNCB pheromone in quantities greater than a gram. Because there is not a bulk commercial source (i.e.  greater than 20 g) of this pheromone available, there is a need to develop a large scale procedure for the PNCB pheromone and to develop an insect-controlling technology to keep the PNCB in check.
A simple method of synthesizing a wide variety of pheromone compounds and precursors that produces high yields and that can be capable of producing stable and reproducible stereoisomeric ratios of products, if needed, is therefore desirable.
An object of the present invention is to provide a synthesis for pheromones or their components that employs a metathesis reaction.
Another object of the invention is, therefore, to improve the process for manufacturing peach twig borer pheromone.
A further object of the present invention is to provide an improved synthesis of mosquito oviposition attractant pheromone.
Yet another object of the present invention is to provide an improved synthesis of pecan nutcase bearer pheromone.
Still another object of the present invention is to provide an improved synthesis of omega haloalkanols and omega haloalkanyl acetates.
FIGS. 1A, 1B, 1C, and 1D (collectively FIG. 1) depict a recent method of producing 5-decenyl acetate disclosed in U.S. Pat. No. 5,916,983 of Pederson and Grubbs. The synthesis produces 1-chlorohexene by coupling allyl magnesium chloride and bromochloropropane. A 40 percent yield of a 60:40 isomeric ratio of trans:cis 1-chloro-5-decene is then obtained by olefin metathesis of 1-chlorohexene and 1-hexene. The metathesis catalyst used in this process is bis(tricyclohexylphosphine)dichloro ruthenium (II) benzylidene, [(PCy3)2Cl2]Ruxe2x95x90CHPh, herein referred to as Catalyst 823, shown in FIG. 2A.
These reactions are performed between 32xc2x0 C. and 62xc2x0 C.; at room temperature, the reaction is slow and conversions are lower. A 27 percent yield is obtained when the reaction is run at 32xc2x0. 1-Chloro-5-decene is converted to 5-decenyl acetate by heating the former with potassium acetate in acetic acid. The resulting 60:40 ratio of trans:cis 5-decenyl acetate is isomerized to an 80:20 ratio of trans:cis 5-decenyl acetate by the sodium salt of benzenesulfinic acid in acetic acid.
The low 25 to 27 percent gross yield of 5-decenyl acetate is largely due to the formation of a methylidene ruthenium catalyst intermediate, which is a thermodynamically stable alkylidene that prevents high conversion of starting materials to products and prevents the formation of a high trans isomeric product.
This method typically requires 18 to 25 days to produce 12 Kg of 5-decenyl acetate in an 80:20 cis:trans ratio using standard-sized equipment (multiple reactions need to be run because of low yields and many of the reactions need to be diluted with solvents to work properly). In particular, five days are typically required to run the reaction and to work up and distill the 1-chloro-5-decene. Three metathesis runs at one day each, plus two days to remove the catalyst, and 2 days to distill, are typically needed to produce the 1-chloro-5-decene for a subtotal of seven days. The subsequent production of 5-decenyl acetate with a trans:cis ratio of 60:40 requires two to three runs at 36 to 48 hours each to achieve 98 percent conversion, for a subtotal of four to six days. Twenty-four hours for each of two batches are required to achieve the isomerization of 5-decenyl acetate to an 80:20 ratio of trans:cis, for a subtotal of two days. The total time of 18 to 25 days does not include the time for the final distillation.
Although the 20 percent cis-5-decenyl acetate does not affect the efficacy of the PTB pheromone in lures and mating disruption applications, the low yield and the long completion time make the process expensive. In view of the numerous reaction steps, the large amount of required starting materials and reagents, the long reaction times, and/or the overall low yield, this manufacturing process for 5-decenyl acetate is still not satisfactory.
The present invention relates, therefore, to metathesis syntheses for a variety of value-added products metathesis in an economical and efficient manner. Most of the cross-metathesis reactions are run neat, and the unreacted starting materials are recycled back into the next cross-metathesis reaction. The invention provides the ability to cross-metathesize two different or similar terminal olefins (i.e. alpha olefin) to produce a new internal olefin, the ability to cross metathesize a terminal olefin and an internal olefin to yield a new internal olefin, the ability to cross metathesize a terminal olefin and a cyclic olefin to yield a new terminal and/or internal olefin, and the ability to cross-metathesize two similar or different internal olefins to yield a new internal olefin product.
Some of the most notable metathesis products facilitated by the invention include insect sex-attractant pheromones or their components, such as E-5-decenyl acetate, the major component of the Peach Twig Borer pheromone; (5R,6S)-6-acetoxy-5-hexadecanolide, the oviposition attractant pheromone; E9,Z11-hexadecadienal, the pecan nut casebearer moth pheromone; 9-tetradecenyl formate, an analog of the Diamondback Moth (DBM) pheromone; 1-tetradecenyl acetate, the Omnivorous Leafroller (OLR) pheromone; E-4-tridecenyl acetate, the major component of the Tomato Pinworm (TPW) pheromone; E,E-8,10-dodecadienol, the Codling Moth (CM) pheromone. The syntheses preferably entail few reaction steps, use generally commercially available starting materials, and have relatively short process times. These syntheses produce good yields without the need for expensive or sophisticated equipment. The invention also provides an inexpensive route for producing omega-haloalkenols by cross-metathesizing alpha-omega-diacetoxy alkenes and alpha-omega-dihalides to yield omega-haloalkenols, which are easily converted into omega-haloalkanols under traditional hydrogenation methods.
The metathesis catalysts preferred for these reactions are selected from Class I-IV metathesis catalysts presented in FIGS. 2, 3, 4, or 5. More preferred metathesis catalysts are those presented in Tables I-IV. The most preferred embodiments employ Catalysts 848, 785, 807, 826, 823, and 801.
The invention particularly provides an improved synthesis of E-5-decenyl acetate that eliminates many of the problems associated with the previous method. In a preferred embodiment, the improvements include: 1) a technique to obtain higher conversion of starting materials to products (from 40 percent to greater than 75 percent); 2) an increase in the metathesis trans:cis ratio from 60:40 to between 80:20 to 84:16; 3) only two reaction steps; and 4) a production time of less than a week.
In one embodiment, certain of these improvements are accomplished by self-metathesizing 1-hexene to 5-decene followed by cross-metathesizing of 5-decene and 5-hexenyl acetate. Both reactions are performed in the presence of the same metathesis catalyst. The self-metathesis of 1-hexene is performed under vacuum so the ethylene side product is allowed to bubble out of solution. The elimination of 1-hexene prevents the formation of the methylidene catalyst intermediate and leads to an increased yield, greater than 98 percent pure 5-decenyl acetate with an 80:20 to 84:16 trans:cis ratio as compared to the earlier 60:40.
The present invention also provides a relatively inexpensive synthetic process for making mosquito oviposition attractant pheromone for the pathogen-vectoring mosquitoes of genus Culex, (5R,6S)-6-acetoxy-5-hexadecanolide. Preferred syntheses of mosquito oviposition attractant pheromone involve the cross-metathesis of commercially available materials, such as meadowfoam oil, hexenoic acid derivatives, hexenal derivatives, or hexenol derivatives with 1-dodecene or 11-docosene, followed by oxidation of the double bond and lactonization. In several embodiments, meadowfoam oil is a preferred starting material because 95% of the oil contains a Z-5-carboxylate moiety, it is commercially available, and it is readily converted to (5R,6S)-6-acetoxy-5-hexadecanolide through metathesis reactions of the present invention.
Additional objects and advantages of this invention will be apparent from the following detailed description of preferred embodiments thereof which proceeds with reference to the accompanying drawings.